Figure 2.

Tetraspanins organize the T-cell immunological synapse. Tetraspanin CD81 regulates the organization of the immunological synapse (IS) in CD4⁺ T lymphocytes through the association with CD3ζ at the central SMAC (cSMAC). CD81 controls the localization of the TCR complex and its downstream signaling, positively modulating the phosphorylation of ZAP-70, LAT, and ERK1/2 (dashed line). At the peripheral area of the cell–cell contact (pSMAC), tetraspanins CD9, and CD151 are important for integrin VLA-4 relocalization and activation, positively regulating the integrin downstream phosphorylation of FAK and ERK1/2 (lines with small dashes). At this location, CD81 also interacts with the adhesion receptor ICAM-1, regulating its segregation during IS maturation. Tetraspanin CD82 accumulates at the pSMAC and triggers actin polymerization and the activation of the Rho GTPase pathway (RhoA, Rac1, and Cdc42). The activation of this pathway induces the phosphorylation and the association of Vav1 and SLP76 (dotted lines), potentiating the phosphorylation of the TCR signaling molecules LAT and ZAP-70. In APCs, CD81 is enriched at the IS and several tetraspanins are described to associate with MHC-II. Moreover, CD151, CD37, and Tssc6 were described to regulate antigen presentation by DCs.